The present invention relates generally to processes for the synthesis of chiral cyclic xcex2-aminoesters, such compounds being useful as intermediates for matrix metalloproteinases (MMP) and TNF-xcex1 converting enzyme (TACE) inhibitors.
The present invention relates to processes for the preparation of chiral cyclic xcex2-aminoesters, which are useful as intermediates in the preparation of MMP and TACE inhibitors. In particular, the present invention provides a process for the preparation of 4-amino-tetrahydro-4H-pyran-3-carboxylate. The general processes disclosed in the art (e.g., C. Cimarelli et al. Tetrahedron-Asymmetry 1994, 5, 1455) provide 4-amino-tetrahydro-4H-pyran-3-carboxylate in low and inconsistent yields of the desired stereoisomer. In contrast to the previously known processes, the present invention provides more practical and economical methodology for the preparation of (3R,4R)-4-aminotetrahydro-4H-pyran-3-carboxylate in relatively high yield and isomeric purity.
The present invention provides access to such xcex2-aminoesters with increased selectivity in the reduction step, resulting in higher yields and isomeric purity of products. In contrast to protocols known in the art using borohydrides as reducing agents (D. Xu et al. Tetrahedron-Asymmetry 1997, 8, 1445), throughput has been increased significantly due to low process volumes. Chiral cyclic xcex2-aminoester products can now be isolated by salt formation directly from the filtered reaction mass, thereby obviating the need for aqueous work-up procedures.
Accordingly, the present invention provides novel processes for making chiral cyclic xcex2-aminoesters.
The present invention provides novel hydrobromide salts of the chiral cyclic xcex2-aminoesters.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors"" discovery that compounds of formula II can be formed from compounds of formula I (* denotes a chiral center). 